Process for the preparation of imidazolones

ABSTRACT

The present invention relates to a process for the preparation of a compound of general formula (I), ##STR1## wherein R 1  represents a hydrogen atom or an alkyl group of 1-6 carbon atoms, and their salts, wherein the compound of formula (II): ##STR2## is reacted with a compound of formula (III): ##STR3## wherein R represents an alkyl group of 1-4 carbon atoms and R 1  is the same as defined above, by heating their neutral pH mixtures at the boiling temperature of the mixture, and the resulting compound of general formula (IV): ##STR4## wherein R and R 1  are the same as defined above, is cyclized into the compound of general formula (I) by further elevating the temperature of the neutral mixture, and if desired, the compounds of general formula (I) are transformed into their salts, or the compounds of general formula (I) are liberated from their salts.

This application is the national phase under 35 U.S.C. §371 of PCTInternational Application No. PCT/HU98/00065 which has an Internationalfiling data of Jul. 22, 1998, which designated the United States ofAmerica.

This invention relates to the new process for the preparation ofcompounds of general formula (I)--wherein R¹ means hydrogen atom oralkyl group of 1-6 carbon atoms--, and to the compounds of generalformula (IV)--wherein R means hydrogen atom or alkyl group of 1-4 carbonatoms and R¹ is the same as defined above.

Compounds of general formula (I) are intermediates of compounds withangiotensin-II antagonist activity which are described in HungarianPatent, No. 211.839 and in the equivalent U.S. Pat. No. 5,270,317.

The above patents, among others, describe a hypotetic reaction route,"reaction scheme B", by this route compounds of general formula (I)might be synthetised from amino-acylamides and ortho esters in acidicmedium. In the above specifications this hypothetic reaction route isnot demonstrated by examples.

For one skilled in the art, in the knowledge of the prior, thishypothetic reaction route, which applies acidic medium, does not seem tobe feasible, since it is known that ortho esters suffer decomposition onthe effect of acids/Houben-Weyl Band VI/3 S 315 (1965)/. It iswell-known, too, that the lone-pair of electron of primary amines inacidic medium is not available for further reactions, as it takes partin the salt formation. It is also known, that in acidic medium primaryamines and ortho esters also give rise to N-aryl- N-alkylformamides,from which the compounds of general formula (I) may not be formed/J. Am.Chem. Soc. 78 p 4778 (1956)/.

BRIEF DESCRIPTION OF DRAWINGS

FIG. 1 describes the imidazolone products of formula (I), the reactantsof formulas (II) and (III) and the intermediates of formula (IV).

In the knowledge of the above we aimed to find a process for thepreparation of compounds of general formula (I) which proceeds in goodyield and results pure product. We found that if the compound of formula(II) is reacted with a compound of general formula (III)--wherein Rmeans an alkyl group of 1-4 carbon atoms and R¹ is the same as definedabove--, by heating their neutral mixtures at reflux temperature, andthe resulting compound of general formula (IV)--wherein R and R¹ are thesame as defined above--, is cyclized into the compound of generalformula (I) by further elevating the temperature of the neutral pHmixture, and if desired, the compound of general formula (I) istransformed into its salt, or the compound of general formula (I) isliberated from its salt, then the compounds of general formula (I) areobtained in very pure condition, in almost theoretical yields, evenapplying just equivalent amounts of reactants.

Our invention furthermore relates to the new compounds of generalformula (IV) which are useful intermediates in the process describedabove.

According to a preferred embodiment of the invention the compound offormula (II) is mixed with a compound of general formula (III), thereaction is carried out at the boiling point of the mixture, theresulting compound of general formula (IV), optionally withoutisolation, is then cyclized by enhancing the temperature of the reactionmixture to 110-160° C., in neutral reaction medium, under conditions ofdistillation or vacuum distillation. When the reaction mixturecontaining the resulting compounds of general formula (I) is acidified,the compounds compounds of general formula (I) are obtained in the formof their acid addition salt.

The compound of formula (II) can be synthetised as described in theabove two patents in Examples 2a and 2b, whereas the compounds ofgeneral formula (III) can be prepared according to J. Am. Chem. Soc. 68p 1923 (1946).

Further details of our process are illustrated by the followingexamples, without limiting our claims to the content of examples.

EXAMPLE 1 2-butyl-1,3-diaza-spiro[4,4]non-1-en-4-one-monohydrochloride

20 g (0.156 mol) of 1-aminocyclopentane-1-carboxamide and 31 g (0.19mol) of trimethyl orthovalerate are refluxed at 70-80° C. innertemperature for 1 hour. The condenser is then changed to a "No hold up"condenser, while heating and stirring are continued to distille offvolatile components. The reaction is completed in vacuo. The residue isdissolved in 150 ml of acetone the pH is adjusted to 1-2, after coolingthe resulting suspension the product is filtered off.

31 g of the title compound is obtained, yield 86.4%.

IR: 3600-2200: vibr, NH; 1779: γc=o; 1642 γc, 1517: δNH (IRFT PerkinElmer)

1H NMR: 0.9 ppm T (CH₃); 1.34 ppm S (CH₂); 1.73 ppm Q (CH₂); 1.78-2.01ppm M cyclopentane (CH₂); 2.78 ppm T (CH₂); 9-15 ppm (NH, N)

MS: 194, 179, 166, 165, 152, 124, 84, 83, 54, 41

TLC: eluent chloroform: methanol=6:1, TLC plate Kieselgel GF254.

Detection: I₂ vapors Rf=0.64

EXAMPLE 2 1,3-diazaspiro[4,4]non-1-en-4-one monohydrochloride

20 g (0.156 mol) of 1-aminocyclopentane-1-carboxamide and 28 g (0.19mol) of trimethyl orthoformate are refluxed for 1 hour. The condenser isthen changed to a "No hold up" condenser, and the temperature iselevated to 140° C. inner temperature. The residue is dissolved in 150ml of acetone the pH is adjusted to 1-2 with concentrated hydrochloricacid and after cooling the resulting suspension the product is filteredof. 25 g of the title compound is obtained, yield 92.2%.

Mp: 219-221° C. (decomp.)

IR: 1663 cm⁻¹ C═N 1739 cm⁻¹ C═O 3197 cm⁻¹ H(NH)

MH⁺ : 139

EXAMPLE 3 N-(1-carboxamidocyclopentyl-1)formimino ethyl ether

12.8 g (0.1 mol) 1-amino-1-carboxamidocyclopentane and 15 g (0.101 mol)of triethyl orthoformate was heated at 80° C. for 1 hour. Volatilematerials formed in the reaction were distilled off in fine vacuum. Theresidual 18 g (97.8%) of oily material was identified by IR and MS asthe title compound.

IR: 1650 cm⁻¹ : CO(CONH) 1625 cm⁻¹ : C═N 3350 cm⁻¹ : H(amide)

MH⁺ : 185

EXAMPLE 4 N-(1-carboxamidocyclopentyl-1)pentaneimino methyl ether

12.8 g (0.1 mol) of 1-amino-1-carboxamidocyclopentane and 16.2 g (0.1mol) of trimehyl orthovalerate was stirred at 80° C. for 1 hour.Volatile materials formed in the reaction were distilled off in finevacuum. The residual 22.6 g (99%) of oily material was identified by IRand MS as the title compound.

IR: 1650 cm⁻¹ : CO(CONH) 1630 cm⁻¹ : C═N 3297 cm⁻¹ : H(amide)

MH⁺ : 227

What is claimed is:
 1. A process for the preparation of a compound ofgeneral formula (I): ##STR5## wherein R¹ represents a hydrogen atom oran alkyl group of 1-6 carbon atoms, and their salts, wherein thecompound of formula (II): ##STR6## is reacted with a compound of formula(III): ##STR7## wherein R represents an alkyl group of 1-4 carbon atomsand R¹ is the same as defined above, by heating their neutral pHmixtures at the boiling temperature of the mixture, and the resultingcompound of general formula (IV): ##STR8## wherein R and R¹ are the sameas defined above, is cyclized into the compound of general formula (I)by further elevating the temperature of the neutral mixture, and ifdesired, the compounds of general formula (I) are transformed into theirsalts, or the compounds of general formula (I) are liberated from theirsalts.
 2. The process as defined in claim 1, wherein the reaction of thecompound of formula (II) with the compound of general formula (III),where R is a methyl group, and R¹ is n-butyl group, is carried out byheating at 70-80° C. under reflux conditions.
 3. The process as definedin claim 1, wherein the resulting compound of general formula (I) istransformed in the reaction mixture into its hydrochloride salt andisolated in the form of this salt.
 4. A compound of general formula(IV): ##STR9## wherein R is an alkyl group of 1-4 carbon atoms and R¹ isa hydrogen atom or an alkyl group of 1-6 carbon atoms. 5.N-(1-carboxamidocyclopentyl-1)-formimino ethyl ether. 6.N-(1-carboxamidocyclopentyl-1)-pentanimino methyl ether.